https://phaidra.vetmeduni.ac.at/o:5407 IFNγ shapes macrophage inflammatory responses by STAT1 isoform-specific epigenetic and transcriptional mechanisms Akagha, Mojoyinola Joanna Mojoyinola Joanna Akagha Georgolopoulos, Grigorios Grigorios Georgolopoulos Martin, David David Martin Meissl, Katrin Katrin Meissl Amenitsch, Lena Lena Amenitsch 0000-0003-4873-1155 Vogl, Claus Claus Vogl 0000-0002-3996-7863 Farlik, Matthias Matthias Farlik Fortelny, Nikolaus Nikolaus Fortelny Halbritter, Florian Florian Halbritter Müller, Mathias Mathias Müller 0000-0002-7879-3552 Decker, Thomas Thomas Decker Strobl, Birgit Birgit Strobl 0000-0001-5716-3212 Springer journal article open access eng Interferon-γ (IFNγ) is a key cytokine that activates macrophages and is essential for the defence against intracellular pathogens. Beyond its immediate effects, IFNγ also shapes macrophages for subsequent encounters with pathogen-associated molecules by multiple mechanisms, including chromatin remodelling. Here, we employed integrated epigenomic and transcriptomic approaches utilizing primary macrophages from gene-modified mice to explore the role of STAT1 and its naturally occurring isoforms in these processes. Using ChIP-seq for histone modifications (H3K27ac and H3K4me1) and RNA-seq, we demonstrate that STAT1 isoforms differentially modulate macrophage responses to lipopolysaccharide (LPS) following IFNγ conditioning. We provide genetic evidence that STAT1 isoforms exhibit distinct capacities to mediated IFNγ-induced changes in H3K27 acetylation at promoter and enhancer regions, thereby shaping transcriptional responses to LPS. We show that the STAT1β isoform, which lacks the C-terminal transactivation domain (TAD), is unable to mediate the repressive effect of IFNγ on transcriptional regulation by LPS but retains significant collaborative activity. Furthermore, we show that IFNγ attenuates the induction of a subset of antiviral genes and represses LPS-induced negative feedback loops, thereby amplifying the inflammatory response to pathogens. These effects are dependent on the presence of the STAT1 C-terminal TAD, highlighting its importance in fine-tuning the balance between inflammatory and antiviral responses. Our findings uncover isoform-specific roles of STAT1 in IFNγ-driven epigenetic regulation and macrophage conditioning, providing new insights into the control of inflammation and innate immunity. Interferon- γ Lipopolysaccharide (LPS) Macrophage Conditioning H3K27ac H3K4me1 RNA-seq http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:5407/download 10.1186/s12864-026-12601-5 https://phaidra.vetmeduni.ac.at/o:605 application/pdf BMC Genomics issn:1471-2164 VoR BMC Genomics 27 1 8.22 MB 2026